PROJECT SUMMARY/ABSTRACT My laboratory has been a leader in taking a broad based approach to studying the role that human papillomaviruses (HPVs) and human polyomaviruses (HPyVs) play in cancer. A major focus has been mechanistic studies to elucidate the contributions of the viral oncoproteins to malignancy. We have identified novel activities of the HPV E6 and E7 proteins including the induction of telomerase activity and inactivation of the p21 CDK inhibitor. For Merkel Cell polyomavirus (MCPyV) we have shown that it defines a new clade of PyVs that contains both primate and rodent PyVs encoding Middle T like proteins. We will explore new data showing that the Small T antigen can transform primary human fibroblasts and cooperate with Ras. We will develop novel mouse models to determine other genetic alterations that cooperate with the viral oncogenes to promote tumorigenicity. These models will be used in innovative ways to test new therapies. Additionally we have led, and participated in, collaborative studies with epidemiologists, statisticians and clinicians to understand the natural history of HPV infections and the host immune response to infection or vaccination. Our current studies focus on understanding the long term memory response to HPV infection to develop better insights into the mechanism of protection of the highly efficacious HPV vaccines, as well as to answer translational questions about optimal vaccine usage. Our overall goal has been, and will continue to be, to find new ways to better prevent, diagnose and treat HPV and HPyV infections that can lead to cancer. We are addressing significant issues, have a proven track record, a wealth of experience and reagents, terrific collaborators and an outstanding environment.